Relationship Between Low SHBG and Low Total Testosterone

Mechanism and Clinical Significance

Low SHBG reduces total testosterone measurements because less testosterone is bound in circulation, while free testosterone (the biologically active form) may remain within normal range 1, 2
In obesity-related hypogonadism, low SHBG is a primary mechanism for decreased total testosterone, with many of these men having normal free testosterone levels 1

High-dose glucocorticoids and exogenous testosterone administration can suppress SHBG production 3
Other conditions associated with low SHBG include Cushing's syndrome, acromegaly, and polycystic ovary syndrome 3

When evaluating low total testosterone, measurement of morning serum free testosterone is essential, especially in men with obesity 1
The diagnosis of testosterone deficiency requires both low testosterone measurements and the presence of symptoms/signs 4, 5
Total testosterone should be measured on two separate occasions in the early morning (between 8-10 AM) 4, 5
A threshold of total testosterone below 300 ng/dL is considered a reasonable cut-off for diagnosing low testosterone 4, 5
Measuring both SHBG and calculating free testosterone index (total testosterone/SHBG ratio) provides better assessment than total testosterone alone in cases of suspected abnormal SHBG levels 3

Men with low total testosterone due solely to low SHBG generally do not require testosterone replacement therapy if free testosterone levels are normal 1, 3
However, a subset of men with obesity will have both low total and free testosterone levels, requiring further evaluation 1
When free testosterone is low despite normal total testosterone, this may be due to increased aromatization of testosterone to estradiol in adipose tissue 1

Measure morning total testosterone (two measurements on separate days) 4, 5
If total testosterone is low (<300 ng/dL), measure SHBG and free testosterone 1, 3
Measure LH and FSH to determine primary vs. secondary hypogonadism 4, 5
If SHBG is low but free testosterone is normal, the low total testosterone is likely due to the SHBG abnormality 1, 3
If both total and free testosterone are low, further evaluation is needed, including serum prolactin measurement in cases of low/normal LH 4, 5

Treatment with testosterone replacement should be considered only when free testosterone is frankly low on at least two separate assessments 1
Weight loss can increase both SHBG and total testosterone levels in men with obesity 1
Addressing underlying causes of low SHBG (such as obesity, insulin resistance) should be the first approach before considering testosterone replacement 3